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March 14, 2017 5:05 pm ET

Only Anti-PD-1 Therapy Approved for the Treatment of Patients with Difficult-to-Treat cHL Regardless of Prior Stem Cell Transplantation or Use of Brentuximab Vedotin

Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
approved KEYTRUDA^® (pembrolizumab), the company’s anti-PD-1
(programmed death receptor-1) therapy, for the treatment of adult and
pediatric patients with refractory classical Hodgkin lymphoma (cHL), or
who have relapsed after three or more prior lines of therapy. Under the
FDA’s accelerated approval regulations, this indication is approved
based on tumor response rate and durability of response. Continued
approval for this indication may be contingent upon verification and
description of clinical benefit in the confirmatory trials. In
refractory or relapsed cHL, KEYTRUDA is approved for use in adult
patients at a fixed dose of 200 mg and in pediatric patients at a dose
of 2 mg/kg (up to a maximum of 200 mg). KEYTRUDA is administered
intravenously every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression.

Immune-mediated adverse reactions occurred with KEYTRUDA including
pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based
on the severity of the adverse reaction, KEYTRUDA should be withheld or
discontinued and corticosteroids administered when appropriate.
Immune-mediated complications, including fatal events, occurred in
patients with cHL who underwent allogeneic hematopoietic stem cell
transplantation (HSCT) after being treated with KEYTRUDA. Follow
patients closely for early evidence of transplant-related complications,
and intervene promptly. KEYTRUDA can also cause severe or
life-threatening infusion-related reactions. Monitor patients for signs
and symptoms of infusion-related reactions; for Grade 3 or 4 reactions,
stop infusion and permanently discontinue KEYTRUDA (pembrolizumab).
Based on its mechanism of action, KEYTRUDA can cause fetal harm when
administered to a pregnant woman. Female patients of reproductive
potential should be advised of the potential hazard to a fetus. For more
information regarding immune-mediated and infusion-related adverse
reactions and use in pregnancy, see “Selected Important Safety
Information” below.

The approval is based on data in 210 patients from the KEYNOTE-087
trial, which demonstrated an overall response rate (ORR) with KEYTRUDA
(200 mg every three weeks) of 69 percent (95% CI: 62, 75) with a
complete remission rate (CRR) of 22 percent and a partial remission rate
(PRR) of 47 percent. The median follow-up time was 9.4 months. Among the
145 responding patients, the median duration of response was 11.1 months
(range 0.0+ to 11.1 months).

“The results from KEYNOTE-087 showed that most patients with relapsed or
refractory classical Hodgkin lymphoma responded to treatment with
KEYTRUDA, and 22 percent experienced complete remission,” said Dr. Roger
M. Perlmutter, president, Merck Research Laboratories. “Today’s approval
– the first for KEYTRUDA in a hematologic malignancy – reinforces the
hope that immunotherapy will prove useful in a wide variety of cancers.”

“For the patients with classical Hodgkin lymphoma who are not cured with
existing treatments, there are limited options, and treating their
disease becomes more challenging,” said Dr. Craig Moskowitz, clinical
director, division of hematologic oncology, Memorial Sloan Kettering
Cancer Center. “This approval is an important step forward in treating
these patients, who are generally young and have a particularly poor
prognosis, and gives us the opportunity to help patients in their fight
against this devastating disease.”

Data Supporting the Approval

The accelerated FDA approval was based on data in 210 patients with
relapsed or refractory cHL enrolled in the multicenter, nonrandomized,
open-label KEYNOTE-087 study. Patients with active, non-infectious
pneumonitis, an allogeneic HSCT within the past five years (or greater
than five years but with symptoms of GVHD [graft-versus-host disease]),
active autoimmune disease, a medical condition that required
immunosuppression, or an active infection requiring systemic therapy
were ineligible for the trial. Patients received KEYTRUDA at a dose of
200 mg every three weeks until unacceptable toxicity or documented
disease progression, or for up to 24 months in patients who did not
progress. The major efficacy outcome measures (ORR, CRR, and duration of
response) were assessed by blinded independent central review according
to the 2007 revised International Working Group (IWG) criteria.
Fifty-eight percent (58%) of patients were refractory to the last prior
therapy, including 35 percent with primary refractory disease and 14
percent whose disease was chemo-refractory to all prior regimens.
Additionally, 61 percent of patients had undergone prior auto-HSCT, 17
percent had no prior brentuximab use, and 36 percent had prior radiation
therapy.

Efficacy analysis showed an ORR of 69 percent (95% CI: 62, 75) with a
CRR of 22 percent and a PRR of 47 percent. The median follow-up time was
9.4 months. Among the 145 responding patients, the median duration of
response was 11.1 months (range 0.0+ to 11.1 months).

KEYTRUDA (pembrolizumab) was discontinued due to adverse reactions in
five percent of 210 patients with cHL and treatment was interrupted due
to adverse reactions in 26 percent of patients. Fifteen percent (15%) of
patients had an adverse reaction requiring systemic corticosteroid
therapy. Serious adverse reactions occurred in 16 percent of patients.
The most frequent serious adverse reactions (≥1%) included pneumonia,
pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients
died from causes other than disease progression; one from GVHD after
subsequent allogeneic HSCT and one from septic shock. The most common
adverse reactions (occurring in ≥20% of patients) were fatigue (26%),
pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%),
and rash (20%).

There is limited experience in pediatric patients. Efficacy for
pediatric patients was extrapolated from the results in the adult cHL
population. In a study of 40 pediatric patients with advanced melanoma,
PD-L1–positive advanced, relapsed, or refractory solid tumors or
lymphoma, patients were treated with KEYTRUDA for a median of 43 days
(range 1-414 days), with 24 patients (60%) receiving treatment for 42
days or more. The safety profile in pediatric patients was similar to
that seen in adults treated with KEYTRUDA. Toxicities that occurred at a
higher rate (≥15% difference) in these patients when compared to adults
under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain
(28%), hypertransaminasemia (28%), and hyponatremia (18%).

About KEYTRUDA

^®

(pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that works by increasing the
ability of the body’s immune system to help detect and fight tumor
cells. KEYTRUDA blocks the interaction between PD-1 and its ligands,
PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both
tumor cells and healthy cells.

KEYTRUDA (pembrolizumab) is administered as an intravenous infusion over
30 minutes every three weeks for the approved indications. KEYTRUDA for
injection is supplied in a 100 mg single-dose vial.

KEYTRUDA Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or
metastatic melanoma at a dose of 2 mg/kg every three weeks until disease
progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA is indicated for the first-line treatment of patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors have high
PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an
FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA is also indicated for the treatment of patients with metastatic
NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an
FDA-approved test, with disease progression on or after
platinum-containing chemotherapy. Patients with EGFR or ALK genomic
tumor aberrations should have disease progression on FDA-approved
therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg
every three weeks until disease progression, unacceptable toxicity, or
up to 24 months in patients without disease progression.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or
metastatic head and neck squamous cell carcinoma (HNSCC) with disease
progression on or after platinum-containing chemotherapy. This
indication is approved under accelerated approval based on tumor
response rate and durability of response. Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA
(pembrolizumab) is administered at a fixed dose of 200 mg every three
weeks until disease progression, unacceptable toxicity, or up to 24
months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients
with refractory classical Hodgkin lymphoma (cHL), or who have relapsed
after three or more prior lines of therapy. This indication is approved
under accelerated approval based on tumor response rate and durability
of response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials. In adults with cHL, KEYTRUDA is administered at a
fixed dose of 200 mg every three weeks until disease progression or
unacceptable toxicity, or up to 24 months in patients without disease
progression. In pediatric patients with cHL, KEYTRUDA is administered at
a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until
disease progression or unacceptable toxicity, or up to 24 months in
patients without disease progression.

Selected Important Safety Information for KEYTRUDA

^®
 (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases.
Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA,
including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%)
pneumonitis, and occurred more frequently in patients with a history of
prior thoracic radiation (6.9%) compared to those without (2.9%).
Monitor patients for signs and symptoms of pneumonitis. Evaluate
suspected pneumonitis with radiographic imaging. Administer
corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA
for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or
recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48
(1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3
(1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms
of colitis. Administer corticosteroids for Grade 2 or greater colitis.
Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for
Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19
(0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3
(0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver
function. Administer corticosteroids for Grade 2 or greater hepatitis
and, based on severity of liver enzyme elevations, withhold or
discontinue KEYTRUDA (pembrolizumab).

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of
2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%),
and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of
hypophysitis (including hypopituitarism and adrenal insufficiency).
Administer corticosteroids and hormone replacement as clinically
indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for
Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism,
hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%)
of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3
(0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799
patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%)
hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients
receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor
patients for changes in thyroid function (at the start of treatment,
periodically during treatment, and as indicated based on clinical
evaluation) and for clinical signs and symptoms of thyroid disorders.
Administer replacement hormones for hypothyroidism and manage
hyperthyroidism with thionamides and beta blockers as appropriate.
Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic
ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients.
Monitor patients for hyperglycemia or other signs and symptoms of
diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA
and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9
(0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3
(0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal
function. Administer corticosteroids for Grade 2 or greater nephritis.
Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for
Grade 3 or 4 nephritis.

KEYTRUDA can cause other clinically important immune-mediated adverse
reactions. For suspected immune-mediated adverse reactions, ensure
adequate evaluation to confirm etiology or exclude other causes. Based
on the severity of the adverse reaction, withhold KEYTRUDA and
administer corticosteroids. Upon improvement to Grade 1 or less,
initiate corticosteroid taper and continue to taper over at least 1
month. Based on limited data from clinical studies in patients whose
immune-related adverse reactions could not be controlled with
corticosteroid use, administration of other systemic immunosuppressants
can be considered. Resume KEYTRUDA (pembrolizumab) when the adverse
reaction remains at Grade 1 or less following corticosteroid taper.
Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse
reaction that recurs and for any life-threatening immune-mediated
adverse reaction.

The following clinically significant immune-mediated adverse reactions
occurred in less than 1% (unless otherwise indicated) of 2799 patients:
arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash
(1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis,
vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising
in a patient with inflammatory foci in brain parenchyma. In addition,
myelitis and myocarditis were reported in other clinical trials,
including cHL, and postmarketing use.

Solid organ transplant rejection has been reported in post-marketing use
of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection
in solid organ transplant recipients. Consider the benefit of treatment
with KEYTRUDA versus the risk of possible organ rejection in these
patients.

KEYTRUDA can cause severe or life-threatening infusion-related
reactions, which have been reported in 6 (0.2%) of 2799 patients.
Monitor patients for signs and symptoms of infusion-related reactions,
including rigors, chills, wheezing, pruritus, flushing, rash,
hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop
infusion and permanently discontinue KEYTRUDA.

Immune-mediated complications, including fatal events, occurred in
patients who underwent allogeneic hematopoietic stem cell
transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients
with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA
on any trial, 6 patients (26%) developed GVHD, one of which was fatal,
and 2 patients (9%) developed severe hepatic veno-occlusive disease
(VOD) after reduced-intensity conditioning, one of which was fatal.
Cases of fatal hyperacute GVHD after allogeneic HSCT have also been
reported in patients with lymphoma who received a PD-1 receptor-blocking
antibody before transplantation. These complications may occur despite
intervening therapy between PD-1 blockade and allogeneic HSCT. Follow
patients closely for early evidence of transplant-related complications
such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD,
steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when
administered to a pregnant woman. If used during pregnancy, or if the
patient becomes pregnant during treatment, apprise the patient of the
potential hazard to a fetus. Advise females of reproductive potential to
use highly effective contraception during treatment and for 4 months
after the last dose of KEYTRUDA (pembrolizumab).

KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients
with cHL and treatment was interrupted due to adverse reactions in 26%
of patients. Fifteen percent (15%) of patients had an adverse reaction
requiring systemic corticosteroid therapy. Serious adverse reactions
occurred in 16% of patients. The most frequent serious adverse reactions
(≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and
herpes zoster. Two patients died from causes other than disease
progression; one from GVHD after subsequent allogeneic HSCT and one from
septic shock. The most common adverse reactions (occurring in ≥20% of
patients) were fatigue (26%), pyrexia (24%), cough (24%),
musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

It is not known whether KEYTRUDA is excreted in human milk. Because many
drugs are excreted in human milk, instruct women to discontinue nursing
during treatment with KEYTRUDA and for 4 months after the final dose.

There is limited experience in pediatric patients. In a study of 40
pediatric patients with advanced melanoma, PD-L1–positive advanced,
relapsed, or refractory solid tumors or lymphoma, patients were treated
with KEYTRUDA for a median of 43 days (range 1-414 days), with 24
patients (60%) receiving treatment for 42 days or more. The safety
profile in pediatric patients was similar to that seen in adults treated
with KEYTRUDA. Toxicities that occurred at a higher rate (≥15%
difference) in these patients when compared to adults under 65 years of
age were fatigue (45%), vomiting (38%), abdominal pain (28%),
hypertransaminasemia (28%), and hyponatremia (18%).

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology
medicines to help people with cancer worldwide. At Merck, helping people
fight cancer is our passion and supporting accessibility to our cancer
medicines is our commitment. Our focus is on pursuing research in
immuno-oncology and we are accelerating every step in the journey – from
lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the
potential of immuno-oncology with one of the fastest-growing development
programs in the industry. We are currently executing an expansive
research program that includes more than 400 clinical trials evaluating
our anti-PD-1 therapy across more than 30 tumor types. We also continue
to strengthen our immuno-oncology portfolio through strategic
acquisitions and are prioritizing the development of several promising
immunotherapeutic candidates with the potential to improve the treatment
of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

For over a century, Merck has been a global health care leader working
to help the world be well. Merck is known as MSD outside the United
States and Canada. Through our prescription medicines, vaccines,
biologic therapies, and animal health products, we work with customers
and operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
health care through far-reaching policies, programs and partnerships.
For more information, visit www.merck.com
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and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the
“company”) includes “forward-looking statements” within the meaning of
the safe harbor provisions of the U.S. Private Securities Litigation
Reform Act of 1995. These statements are based upon the current beliefs
and expectations of the company’s management and are subject to
significant risks and uncertainties. There can be no guarantees with
respect to pipeline products that the products will receive the
necessary regulatory approvals or that they will prove to be
commercially successful. If underlying assumptions prove inaccurate or
risks or uncertainties materialize, actual results may differ materially
from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry
conditions and competition; general economic factors, including interest
rate and currency exchange rate fluctuations; the impact of
pharmaceutical industry regulation and health care legislation in the
United States and internationally; global trends toward health care cost
containment; technological advances, new products and patents attained
by competitors; challenges inherent in new product development,
including obtaining regulatory approval; the company’s ability to
accurately predict future market conditions; manufacturing difficulties
or delays; financial instability of international economies and
sovereign risk; dependence on the effectiveness of the company’s patents
and other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause results
to differ materially from those described in the forward-looking
statements can be found in the company’s 2016 Annual Report on Form 10-K
and the company’s other filings with the Securities and Exchange
Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information for KEYTRUDA (pembrolizumab) at 

http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

 and

Patient Information/Medication Guide for KEYTRUDA at 

http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf

.

Merck
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